tbuckley/cabot-search huggingface dataset:
P17.15.A Neoadjuvant immunotherapy in the treatment of recurrent glioblastoma: an overview of last decade
Authors: B V Nogueira, A Cyntia Fonseca Lima Rodrigues, I M Almeida
Journal: Neuro-Oncology (2022)

Abstract Background Recurrent glioblastoma (ArGB) is one of the most common primary malignant brain tumors in adults, with a poor prognosis, with low patient survival even after treatment. Because of this, several studies were carried out evaluating different therapies for the treatment of ArGB, more recently studies have emerged regarding the use of neoadjuvant immunotherapy and its possible advantages in the treatment of such patients. Therefore, the present study aims to analyze the efficacy of neoadjuvant immunotherapy and its effect on the survival of patients with recurrent glioblastoma. Material and Methods A search was performed in PubMed, Embase and Cochrane databases using the keywords: “Immunotherapy, “neoadjuvant” and "recurrent glioblastoma". Articles from the last 10 years were selected and those that did not meet the inclusion criteria were excluded from the research, totaling 7 selected articles. Results Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy after surgery, had significantly prolonged survival compared to patients who were randomized to receive adjuvant post-surgical PD-1 blockade alone. Neoadjuvant PD-1 blockade was associated with up-regulation of T cells and interferon-γ-related gene expression, but with down-regulation of cell cycle-related gene expression within the tumor, which was not observed in patients receiving adjuvant therapy. isolated. Conclusion Neoadjuvant immunotherapy, through a PD-1 inhibitor, in patients with ArGB, results in positive biological effects, in addition to the clinical benefit of, on average, increasing overall survival considerably due in large part to the improvement of the immune response , with no noticeable adverse effects, thus being advantageous, although these results are early and the current studies are not very comprehensive. Larger studies are needed for greater reliability and statistical relevance.
P11.17.B Molecular characterization of primary central nervous system lymphoma vs non-CNS lymphoma and correlation between mutational profile and treatment response
Authors: K J Tuohy, B Wirk, D Aregawi, J Xiu, A Sumrall, M Glantz
Journal: Neuro-Oncology (2022)

Abstract Background Primary central nervous system lymphoma (PCNSL) is a unique type of non-Hodgkin lymphoma restricted to the central nervous system. Most cases are diffuse large B-cell lymphomas, but prognosis is far less favorable compared to extracerebral cases. Many mutations found in PCNSL converge on the NF-κB signaling pathway, leading to downstream activation of B-cell receptor (BCR) and NF-κB pathway. The differences in mutation frequency when compared to non-CNS lymphoma and how mutational profiles affect treatment response are not well understood. We compared the genomic profile of PCNSL and non-CNS lymphoma, evaluated the association between specific molecular alterations and survival, and analyzed the association between various mutations and response to therapy. Materials and Methods A total of 60 patients with PCNSL, 8 with secondary CNS lymphoma, and 202 with non-CNS B-cell lymphomas underwent molecular profiling at Caris Life Sciences (Phoenix, AZ). Analyses included next-generation sequencing of DNA (592 Genes, NextSeq or WES, NovaSeq) and RNA (WTS, NovaSeq). X2/Fisher’s-exact U tests were used for comparison, and significance was determined as p-value adjusted for multiple comparison by the Benjamini-Hochberg method (q&amp;lt;0.05). Overall survival (OS) was calculated from the start of temozolomide (TMZ) or tissue collection to last contact using insurance claims data. Results When compared to non-CNS lymphomas, PCNSL tumors showed significantly higher mutation rates in MYD88 (70% vs. 7%), PIM-1 (58% vs. 7%), CD79B (42% vs. 3%) and higher rates of TMB-High (cutoff 10mut/MB; 28% vs. 10%) (q&amp;lt;0.01). In addition, mutations in CARD11 (12% vs. 4%) and IRF4 (8% vs. 1%) trended to be more prevalent in PCNSL (p&amp;lt;0.05). In contrast, mutations in KMT2D (35% vs. 16%), EZH2 (13% vs. 2%), CREBBP (22% vs. 7%), TNFRSF14 (10% vs. 0) and BCL2 (19% vs. 2%) trended to be more prevalent in non-CNS lymphomas compared to PCNSL (p&amp;lt;0.05). In patients with PCNSL, there was no difference in survival in those with or without MYD88, PIM1 or CD79B mutations. No between-group differences were observed in the small cohort of patients with secondary CNS lymphoma (n=8). In the subgroup in whom these data were available, 25% of tumors were MGMT methylated, 71% had a “high or intermediate” tumor mutational burden, 8% were MSI high, and 54% were PD-L1 expression positive when tested by immunohistochemistry. Patients with PCNSL had worse overall survival (OS) than non-CNS lymphomas (30 vs 81 months, p&amp;lt;0.001). Conclusion MYD88, PIM-1, and CD79B mutations are more frequent in PCNSL compared to non-CNS lymphomas, but none of these mutations affected OS. Only 25% of PCNSL patients are MGMT methylated, but a majority have expression of PD-L1 suggesting a benefit from PD-1-targeted therapy. Response and survival in patients with mutation-guided therapy will be presented.
P08.12.B Conceptual development of an intensive supervised exercise program for brain tumor patients: summary of clinical experience
Authors: J Jost, R Brandt, U Altuner, M Müther, W Stummer, K Völker, R Wiewrodt, D Wiewrodt
Journal: Neuro-Oncology (2022)

Abstract Background Several studies have identified beneficial effects of physical activity on reducing cancer-related symptoms. However, the number of such studies in neuro-oncology is limited, and even today, brain tumor patients are often advised against physically strenuous exercise. Here we summarize our experience with an individualized training program in brain tumor patients over a period of more than 8 years. Material and Methods Patients with primary brain tumors were invited to participate in the individual training program as part of the psycho-oncological consultation. If interested and free of major comorbidity, a professional sport scientist/diploma coach individualized two 60-minute sessions/week adapted to the patients’ respective symptoms and trained them on a 1:1-basis. One session consisted of bicycle ergometry at an average workload of 75% of the max. age-adjusted heart rate (up to 95% at peak; continuous monitoring throughout entire session), the other session was progressive whole-body resistance training based on 10 separate, but standardized exercise tasks using the university’s training facilities. Both training sessions were complimented by challenging elements to improve coordination. Exercise tasks were adapted as needed, and exercise levels were enhanced over time, if possible. Results From 2011 to 2019, 45 patients (19 women, 26 men) aged 20-76 years (mean 49) with different tumor types (65% high-grade gliomas, 22% low-grade gliomas, 13% other) participated in the program. The majority of patients started the program following concurrent radio-chemotherapy and in parallel with adjuvant systemic therapy. On average, 41 training sessions were performed. No training-related adverse events (e.g., falls, head pain, etc.) occurred during the entire period. In a total of 1828 training sessions, two minor epileptic seizures occurred (1 speech arrest; 1 simple focal seizure, left hand affected). Both patients were familiar with the respective type of seizure before entering the program and training could be continued immediately, with reduced intensity. Seizures did not reoccur during subsequent training sessions. Conclusion This supervised intensive physical training program with submaximal exertion zones was feasible, safe, and highly rated by all participants. Based on these experiences and the reported well-being of the patients, we launched a prospective oligocentric study to objectify the improvements in physical performance and quality of life in patients with glioblastoma (ClinicalTrials.gov Identifier: NCT05015543).
P10.05.B Platelet-derived growth factor signalling pathways in patient-derived glioblastoma cells
Authors: S Y Li, P Schweder, J Correia, T I Park, M Dragunow
Journal: Neuro-Oncology (2022)

Abstract Background Platelet-derived growth factor (PDGF) signalling is essential in the development and maintenance of the neurovasculature. Of particular importance is PDGFRβ signalling for the recruitment and maintenance of the mural cell type pericytes, which occupy an important position in coordinating blood-brain barrier functions. The PDGF pathway is also implicated in glioblastoma, where overexpression of PDGFRα is a signature of the proneural subtype of the highly malignant and invasive tumour. The expression and signalling of both PDGFRα and β by tumour cells have been implicated in tumorigenesis and progression. Therefore, we sought to study PDGF receptor signalling in primary human-derived glioblastoma tumour cells to gain a better understanding of the signalling mechanisms driven by these receptors. Material and Methods Primary human epilepsy pericytes and glioblastoma tumour cells were isolated from surgical resections obtained from consenting patients at Auckland City Hospital. PDGF signalling pathways were investigated through treatment with exogenous PDGF ligands. Pathway activation was quantified using immunocytochemistry, human cytokine XL Proteome Profiler and cytometric bead arrays. Results PDGF-BB and PDGF-DD treatment led to the activation of PDGFRβ in pericyte cultures, which mediated the activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt cascades, ultimately increasing pericyte proliferation and cytokine secretion. PDGF-AA treatment resulted in transient MAPK activation, but was not followed by increased proliferation in pericytes. In contrast, although PDGF-AA, -BB and -DD induced PDGFRα internalisation (and PDGF-BB and -DD induced PDGFRβ internalisation) in GBM tumour cells, this did not result in MAPK or PI3K/Akt activation or cell proliferation. Conclusion Despite PDGF receptor expression, the GBM tumour cells, in contrast to pericytes, surprisingly displayed a lack of responses to ligand stimulation through either PDGFRα or PDGFRβ. This warrants further investigation into the signalling mechanisms behind tumour cells to better understand tumour biology.
P11.44.A The impact of heme biosynthesis regulation on glioma aggressiveness: correlations with most recent diagnostic molecular markers
Authors: M Mischkulnig, B Kiesel, T Rötzer-Pejrimovsky, M Borkovec, A Lang, M Millesi, L I Wadiura, S Hervey-Jumper, J M Penninger, M S Berger, G Widhalm, F Erhart
Journal: Neuro-Oncology (2022)

Abstract Background The prognosis of patients with diffusely infiltrating gliomas is dismal but varies greatly between individuals. While characterization of gliomas was primarily relied on typical histopathological features, specific molecular markers increasingly gained importance and play a key role in the recently published 5th edition of the World Health Organization (WHO) classification. Heme biosynthesis represents a crucial pathway due to its key role in oxygen transport, energy production or drug metabolism. Recently, we described a “heme biosynthesis mRNA expression signature” that correlates with histopathological glioma grades and patient survival. The aim of the current study was to correlate the heme biosynthesis mRNA expression signature with the most recent diagnostic molecular markers for glioma stratification. Material and Methods In this study, patient data were derived from the “The Cancer Genome Atlas” (TCGA) lower-grade glioma and glioblastoma cohorts. We identified diffusely infiltrating gliomas correlating molecular tumor diagnosis according to the most recent WHO classification with heme biosynthesis mRNA expression. The following molecular markers were analyzed: EGFR amplification, TERT promoter mutation, CDKN2A/B homozygous loss, concurrent chromosome 7 gain/10 loss, MGMT methylation, IDH mutation, ATRX loss, p53 mutation and 1p19q co-deletion. Subsequently, we calculated the heme biosynthesis mRNA expression signature and correlated this signature with distinct molecular glioma markers as well as the resulting molecular subgroups. Results A total of 649 patients with available data on up-to-date molecular markers and heme biosynthesis mRNA expression were included. According to analysis of individual molecular markers, we found a significantly higher heme biosynthesis mRNA expression signature in gliomas with IDH wildtype (p&amp;lt;0.0005), without 1p19q co-deletion (p&amp;lt;0.0005), with homozygous CDKN2A/B loss (p&amp;lt;0.0005) and with EGFR amplification (p=0.001). Furthermore, we observed that the heme biosynthesis mRNA expression signature increased with the aggressiveness of the molecular subgroups (p&amp;lt;0.0005), being lowest in WHO grade 2 oligodendrogliomas and highest in WHO grade 4 glioblastomas. Conclusion Our data demonstrate a significant correlation between diagnostic molecular markers and heme biosynthesis regulation in diffusely infiltrating gliomas. Consequently, heme biosynthesis expression is a promising biomarker for glioma aggressiveness and might constitute a potential target for novel therapeutic approaches.
P01.18.B Structural abnormalities related to chemotherapy in cancer survivors: an ALE meta-analysis of neuroimaging studies
Authors: Y Ahmed, A Al-Bzour, G Al-Majali, O Ababneh, R Ibrahim, A Al-Khalili, A Hamza, S Alzghoul, R Al-Mannai, K Z Alawneh, K Al-Hayek, M Al Qawasmeh
Journal: Neuro-Oncology (2022)

Abstract Background Chemotherapy induced cognitive impairment (CICI) is a term used for the cognitive dysfunction reported with non-central nervous system cancer patients during or after chemotherapy. Recent neuroimaging studies have shown decreased activation in cancer patients during cognitive tasks post-chemotherapy. Structural changes are sought to be associated with cognitive decline in cancer survivors after chemotherapy. Here we aim to investigate the neuroimaging findings of structural abnormalities and gray matter alterations associated with chemotherapy in cancer survivors. Material and Methods A systematic search through PubMed database for peer-reviewed English-language studies yielded a total of 302 studies. Eligible studies were included in the activation likelihood estimation (ALE) meta-analysis if they reported coordinates in a stereotactic format (MNI or Talairach space) for voxel-based morphometric (VBM) studies on gray matter volume and post-chemotherapy cancer survivors compared to matched healthy controls. GingerALE (3.0.2) software from Brainmap.org was used to perform the ALE meta-analysis with threshold settings of uncorrected P-value &amp;lt; 0.001 for multiple comparisons. Results The study sample included 299 patients comprised of breast cancer survivors (BCS), childhood acute lymphocytic leukemia (ALL) survivors, ovarian cancer survivors (OCS) and lung cancer with 279 matched healthy controls from 12 studies and 21 experiments. ALE-maps for post-chemotherapy cancer survivors showed reduced gray matter volume in comparison to healthy controls in the left inferior frontal gyrus, right thalamus, right superior frontal gyrus, right medial frontal gyrus and right cerebellum (peak coordinates: [-43,40,-6], [23,-29,2], [14,30,55], [9,57,-16], [9,-78,-41] respectively, and cluster size of 544 mm3, 312 mm3 and 257 mm3, 296 mm3, 297 mm3 respectively). Conclusion This is the first ALE meta-analysis that studied the converged areas of reduced gray matter volume in post-chemotherapy cancer survivors. Our findings of reduced gray matter volume in frontal regions and cerebellum might be responsible for the cognitive dysfunction in executive function, attention, and memory observed in cancer survivors. Further studies are needed to assess the impact of different chemotherapeutic regimens related to CICI .
KS05.5.A Alterations in white matter fiber density associated with structural MRI and metabolic PET lesions following multimodal therapy in glioma patients
Authors: M Friedrich, E Farrher, S Caspers, P Lohmann, G Stoffels, C Filss, C Weiss Lucas, M I Ruge, K J Langen, N J Shah, G R Fink, N Galldiks, M Kocher
Journal: Neuro-Oncology (2022)

Abstract Background In glioma patients, multimodal therapy and recurrent tumor result in local brain tissue changes, characterized by pathologic findings in structural MRI and metabolic PET images. Little is known about these different lesion types’ impact on the local white matter fiber architecture and clinical outcome. Patients and Methods This study included data from 121 pretreated patients (median age, 52 years; ECOG, 01) with histomolecularly characterized glioma (WHO grade IV glioblastoma, n=81; WHO grade III anaplastic astrocytoma, n=28; WHO grade III anaplastic oligodendroglioma, n=12), who had a resection, radiotherapy, alkylating chemotherapy, or combinations thereof. After a median time of 14 months (range, 1-214 months), post-therapeutic structural and metabolic findings were evaluated using anatomical MRI and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET acquired on a 3T hybrid PET/MR scanner. Local fiber density was estimated from tractography based on highangular resolution diffusion-weighted imaging. A cohort of 121 healthy subjects selected from the 1000BRAINS study and matched for age, gender and education served as a control group. Results The median volume of resection cavities, contrast-enhancing regions, regions with pathologically increased FET uptake, and T2/FLAIR hyperintense regions amounted to 20.9, 7.9, 30.3, and 53.4 mL, respectively. Compared to the control group, the average local fiber density in these regions was significantly reduced (p&amp;lt;0.001). Resection cavities showed the highest reduction, followed by contrast-enhancing lesions and metabolically active tumors on FET PET (relative fiber density reduction, -87%, -65%, -55%, respectively). The local fiber density was inversely related (p=0.005) to the FET uptake in recurrent tumors. T2/FLAIR hyperintense lesions, either assigned to peritumoral edema in recurrent glioma or radiation-induced gliosis, had a comparable impact on reducing fiber density (48% and 41%, respectively). The total fiber loss (average fiber loss multiplied by lesion volume) associated with contrast-enhancing lesions (p=0.006) and T2/FLAIR hyperintense lesions (p=0.013) had a significant impact on the general performance status of the patients (ECOG score). Conclusions Our results suggest that apart from resection cavities, reduction in local fiber density is greatest in contrast-enhancing recurrent tumors, but total fiber loss induced by edema or gliosis has an equal detrimental effect on the patients’ performance due to the larger volume affected. Funding Funded by the 1000BRAINS study (INM, Research Centre Juelich, Germany), Horizon 2020 (Grant No. 945539 (HBP SGA3; SC)), and Heinz Nixdorf Foundation.
P11.08.A Clinical practice evidence for perampanel in epilepsy patients with tumour aetiology
Authors: A Coppola, S Izumoto, X Rodríguez-Osorio, T Wu, W D’Souza, M Maschio, S Goldman, M Valente Fernandes, V Villanueva
Journal: Neuro-Oncology (2022)

Abstract Background Real-world studies can provide information on those patients routinely excluded from clinical trials such as epilepsy patients with tumour aetiology. Perampanel (PER) is a once-daily oral anti-seizure medication for focal-onset seizures, with or without focal to bilateral tonic-clonic seizures, and generalised tonic-clonic seizures. This study evaluated PER’s effectiveness and safety when used in everyday clinical practice to treat epilepsy patients with tumour aetiology. Material and Methods Patients with epilepsy with tumour aetiology were identified from a pooled analysis of 44 prospective/retrospective/cross-sectional clinical practice studies. Retention was assessed after 3, 6 and 12 months of PER treatment. Effectiveness assessments comprised responder rate (≥50% seizure frequency reduction), seizure freedom rate (no seizures since at least the prior visit), and the proportions of patients with unchanged or worsening seizure frequency. Adverse events (AEs), psychiatric AEs, and AEs leading to discontinuation were also evaluated. Results Overall, 127 patients with focal-onset and/or generalised-onset seizures with tumour aetiology were identified (mean age, 46.6 years; 54.8% male; mean duration of epilepsy, 9.7 years). Seizure types at baseline were focal-onset only (97.6%), generalised-onset only (1.6%), and focal-onset and generalized-onset (0.8%). Mean (standard deviation) PER doses at baseline and last visit were 2.6 (1.4) and 5.8 (2.5) mg/day, respectively. At 3, 6 and 12 months, retention rates were 88.0%, 79.5% and 65.3%, respectively. Reasons for discontinuation included AEs (16.8%) and lack of efficacy (5.3%). Mean time under PER treatment was 11.0 months. At 12 months, 71.2% of patients were responders and 38.3% were seizure free; 11.9% and 3.4% of patients had unchanged and worsening seizure frequency, respectively. At the last visit (last observation carried forward), responder and seizure freedom rates were 66.9% and 34.2%, respectively, and the percentages of patients with unchanged or worsening seizure frequency were 15.3% and 6.8%, respectively. AEs were reported for 36.2% of patients, most frequently dizziness/vertigo (13.8%) and somnolence (9.5%). AEs led to discontinuation of 16.8% of patients over 12 months and 13.0% of patients experienced psychiatric AEs. Conclusion PER was effective and generally well tolerated when used to treat patients with epilepsy with tumour aetiology in clinical practice. Supported by Eisai